The impact of alanyl-glutamine on clinical safety, nitrogen balance, intestinal permeability, and clinical outcome in postoperative patients: A randomized…

Jiang, Zhu Ming

Glutamine is the principal fuel utilized by the intestinal mucosal cells.1 The small intestine consumes far more circulating glutamine than any other amino acid. However, stores of glutamine are labile, and alterations in plasma concentration are closely relative to intestinal mucosal structure and function.

Studies in patients undergoing major elective surgery have shown that infusion of alanine-glutamine (Ala-Gln)-supplemented parenteral nutrition (PN) over 5 days resulted in an improvement of the nitrogen balance on each postoperative day compared with controls receiving isonitrogenous and isocaloric PN without the peptide.2 The improved net nitrogen balance was associated with maintenance of the intracellular glutamine pool, whereas in patients receiving the control solution glutamine levels were markedly decreased compared with preoperative values. In agreement with these results, IV supply of Ala-Gln or free Gln after cholecystectomy preserved the intracellular glutamine pool (91% of preoperative value), and the characteristic postoperative change in muscle ribosome profile was abolished.3,4

In patients with inflammatory bowel disease and neoplastic disease, intestinal permeability (by the LIM ratio method) could be maintained and villus height preserved with Gln-dipeptide supplementation. However, knowledge of the effect of Ala-Gln on intestinal permeability and clinical outcome in major surgical patients on a large scale is minimal.

The purpose of this study was to evaluate the impact of Ala-Gln-supplemented PN on clinical safety, nitrogen balance, intestinal permeability, and clinical outcome in postoperative patients. In China, this was the first clinical study with Ala-Gln dipeptide.


Subjects and Study Design

This was a randomized, double-blind, controlled, parallel multicenter clinical trial in Beijing and Shanghai. The study period was from May 1997 to April 1998. Major gastrointestinal surgery patients who needed PN for 6 days were enrolled.

The randomization table from each center was prepared by Fresenius Medical Department using the table from randomization software (NDTS Statistic software, approved by Drug Administration Bureau).6 Patients satisfying the enrollment criteria received an ascending serial number in the order of their enrollment. Based on this number, the patients were assigned to one of the two study groups. The patient number appeared on the patient’s prescription and was used to prepare the All-in-One bag for the patient. The preparation of double-blind solutions was conducted with the help of the pharmacy. The patient number was printed on the outside of the medication package.

The clinical safety studies were performed in 120 patients. In 60 patients, nitrogen balance, intestinal permeability, and clinical outcome were determined.

Feeding Regimen

The 2 groups were isonitrogenous and isocaloric. Nitrogen intake was 0.2 g/kg body wt per day. Caloric intake was 30 kcal/kg body wt; glucose calories:fat calories = 1:1 and N:kilocalories = 1:150. The study group was given Ala-Gln (0.50 g/kg per day + MoriProne-F 0.68 g/kg per day) (100 mL of Ala-Gln 20% contain 20 g N(2)-L-alanyl-:L-glutamine, equivalent to 8.18 g L-alanine and 13.42 g L-glutamine, respectively), and the control group only received Moriprone-F (1.3 g/kg per day, Moriprone-F: balanced amino acid solutions, Morishita Licensed Product by Tianjin AA Co). After mixing in a 3-L bag, the solutions were infused by regular central line or by peripherally inserted central catheter (PICC) line for 6 days. Patients

The patient characteristics are shown in Table I. Reference Parameter, Surrogate Efficacy Parameters, and

Clinical Outcome

Plasma amino acid profiles were performed to evaluate the patients for imbalance. The L/M ratio, nitrogen balance, and the cumulative nitrogen balance were obtained over the 6 study days to evaluate efficacy. The clinical outcome was evaluated by determining length of hospital stay.

Nitrogen balance. For the assessment of the total-N of intake and output, a standard method of nitrogen determination was used (semimicro-Kjeldahal method). Tests were performed in the laboratories in 3 hospitals. Quality control was conducted in Clinical Pharmacology Research Base, Department of Surgery, Peking Union College Hospital. Lyphochek (Bio-Rad, CA) was used as control standard.

The cumulative nitrogen balance for 6 days was described as N^sub cum^ and N^sub bal^ = N^sub in^ – N^sub out^ No correction. L/M Ratio. Intestinal permeability evaluation: L = 6-hour excretion rate of lactulose in the urine; M = 6-hour excretion rate of mannitol in the urine. The detection of lactulose and mannitol was done by PADHPLC (Dionex, USA). The analysis was performed in the Laboratory of Surgical Nutrition and Metabolism, Peking Union Medical College Hospital.

Plasma amino acid profile. Plasma amino acids were determined by Beckman AA Analyzer (Peking Union College Hospital), Waters HPLC (Beijing Hospital), or Hitachi AA analyzer (People’s Hospital) in Beijing,China. Quality control was conducted in Clinical Pharmacology Research Base, Department of Surgery, Peking Union College Hospital. Standard solutions for quality control were from Beckman (CA) and Lyphocheck.

Assessment of Safety

Laboratory parameters. The following routine laboratory tests were performed at each hospital.

Hematology: hemoglobin, white blood cell (WBC) count, platelets, and differential WBC (neutrophils, lymphocytes). Chemistry: sodium, potassium, chloride, GPT (ALT), alkaline phosphatase, glucose, cholesterol, urea, creatinine, total bilirubin, triglycerides, and standard bicarbonate. Urine analyses: volume of 24-hour urine for N-balance (10-mL aliquot), 6-hour urine for LIM ratio (5- to 10-mL aliquot).

Infection rate. The infection rate was assessed according to the definitions of American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference (ACCP/SCM) for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.

This study was conducted according to the principles of the Declaration of Helsinki/Hong Kong of 1989, EC-GCP and AM GCP guidelines, and Chinese GCP guidelines. The protocol and informed consent were approved by the appropriate Ethics committee of each center.


All statistical analyses were performed on a Power Mac computer with Statview statistical software.7 Analysis of variance (ANOVA) was used to determine differences of digital data between groups. Counting data (such as sex, complication rate) were analyzed by X^sup 2^ test. Data were represented as means S+/-D. Values were considered statistically significant at p



The results showed that after 6 days of amino acid infusion, all the parameters of safety, including vital signs, blood routine, liver and kidney function, serum lipids, and systemic side reactions were similar in both groups. Clinical chemistry comparison of the two groups before and after the infusion of different amino acids are shown in Table II.

Glutamine Concentration

The concentration of glutamine increased in the study group. The A between the study group before operation (AOD-3) and postoperative day 7 (POD+7) was significantly better than that in the control group (-86 +/- 85.3 vs 45.3 +/- 104.3, p = .001) (Table III; Fig. 1).

Nitrogen Balance

The patients in the study group gained positive nitrogen balance. The cumulative nitrogen balance was 144.3 +/- 145.6 mg/kg per 6 days and -5.1 + 162.7 mg/kg per 6 days in the study and control groups, respectively. Their difference was significant (p = .0004) (Table IV; Fig. 2).

L/M Ratio

L/M ratios were 0.047 + 0.029 in control and 0.058 + 0.049 in study groups AOD-3. Lf/M ratios in control and study groups were 0.132 0.081 and 0.097 0.063, respectively, on POD+7. The A of L/M between the 3rd day before the operation and POD+7 were as follows: study group, 0.039 0.072; control group, 0.084 0.072. Their difference was significant (p = .02) and the study group was better than the control group (Table V; Fig. 3).

Clinic Infection Rate

There were no wound infections in either group, and there were only 3 cases of infection-related complication in the control group (5%), but there were no significant differences (X^sup 2^ = 3.16, p = .24) compared with the study group.

Hospital Stay

The hospital stay in the study group was 12.5 + 5.1 days, which was 4 days less than that of the control group (16.4 7.1 days) (p = .02) (Table VI; Fig. 4).


We have used a prospective, double-blind and randomized treatment plan to compare the PN enriched with Ala-Gln or without Ala-Gln in safety and efficacy in terms of nitrogen balance, intestinal permeability, and clinical outcome. Studies from our group showed that L-alanyl-i-glutamine (Ala-Gln) and glycyl-L-glutamine (Gly-Gln) were stable.s89 In this study, the glutamine and alanine concentrations in the study group were significantly higher than those of control group, suggesting that Ala-Gln can be utilized and released to glutamine and alanine effectively. Our results showed that in the study group, the nitrogen balance and the intestinal permeability were better than those in the control group, which were similar to the results of other studies using glutamine dipeptide.35

The Gln concentration, nitrogen balance, intestinal permeability, and clinical outcome showed a significant difference between the study and the control groups. We concluded that Ala-Gln-supplemented PN was safe, had better nitrogen balance, and maintained intestinal permeability in postoperative patients. Major trauma and operative patient groups would benefit from the parenteral feedings enriched with Gln.


This work was supported by the Ministry of Public Health of China, Grant 9701204, and by Fresenius AG, Germany.

Copyright American Society for Parenteral and Enteral Nutrition Sep/Oct 1999

Provided by ProQuest Information and Learning Company. All rights Reserved.

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